ABSTRACT: Macrophages are central cellular effectors of both injurious and reparative cellular responses in myocardial infarction (MI). The diverse roles of macrophages in MI reflect both their heterogeneity, and their phenotypic transitions in response to the changes in the cytokine environment of the infarct. Understanding the key molecular effectors of infarct macrophage activation has major therapeutic implications. Colony-Stimulating Factor (CSF)-1 is a central effector of macrophage survival, differentiation, proliferation and anti-inflammatory transition and signals through the CSF-1 receptor (CSF-1R). Although descriptive studies have demonstrated high CSF-1 expression in healing infarcts, its role in the phenotypic transitions of infarct macrophages remains poorly understood. The current proposal investigates the role of the CSF-1/CSF-1R axis in repair and remodeling after MI, dissects the molecular mechanisms of CSF-1 actions and explores the therapeutic potential of CSF-1 targeting. Our preliminary data suggest that in healing infarcts, fibroblasts are the main source of CSF-1, whereas CSF-1R is almost exclusively expressed by macrophages. Bioinformatic analysis of our scRNA-seq data identified CSF-1 as the top-ranked upstream regulator responsible for transcriptional activation of the main reparative population of infarct macrophages. Accordingly, we will use cell-specific loss-of-function approaches in vivo, single cell transcriptomics and in vitro assays to test the hypothesis that a CSF-1/CSF-1R-dependent fibroblast-macrophage axis plays a central role in repair of the infarct and to dissect the molecular pathways involved in CSF-1R-mediated macrophage modulation. Furthermore, our preliminary data suggest that early CSF-1 administration attenuates dysfunction in a model of reperfused MI and inhibits inflammatory activation of infarct macrophages. Thus, we will explore the therapeutic effects of early activation of CSF-1/CSF-1R to improve repair and attenuate adverse remodeling after MI. The role and therapeutic potential of the CSF-1/CSF-1R axis in the infarcted heart will be studied in 4 specific aims: Aim 1: To examine the in vivo effects of macrophage-specific CSF-1R activation in repair and remodeling of the infarcted heart. Aim 2: To investigate the role of fibroblast-derived CSF-1 in repair and remodeling of the infarcted heart using fibroblast-specific KO mice. Aim 3: To examine the therapeutic effectiveness of early activation of the CSF-1/CSF-1R axis in reperfused and non-reperfused MI. Aim 4: To study the molecular circuitry of CSF-1/CSF-1R-mediated infarct macrophage activation. The proposed studies will dissect for the first time the role of the CSF-1/CSF-1R axis in MI, and will explore early CSF-1 treatment as a novel therapeutic strategy to accelerate and improve cardiac repair.

NARRATIVE: Repair of the infarcted heart requires timely recruitment and activation of macrophages. Cytokines and growth factors are involved in regulation of infarct macrophage phenotype and function. Our proposal examines for the first time the role of the growth factor Colony Stimulating Factor (CSF)- 1 in repair and remodeling of the infarcted heart. We will test the hypothesis that CSF-1 is secreted by infarct fibroblasts and activates a reparative phenotype in macrophages, acting through CSF- 1R. We will also examine the therapeutic effectiveness of early therapy with CSF-1 to improve repair and attenuate remodeling after infarction.